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The effect of inorganic nitrate and antiplatelet drugs on NO metabolites and platelet reactivity in patients with stable coronary artery disease

Abdul, Fairoz 2019. The effect of inorganic nitrate and antiplatelet drugs on NO metabolites and platelet reactivity in patients with stable coronary artery disease. MD Thesis, Cardiff University.
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Abstract

P2Y12 antagonists are commonly prescribed in coronary artery disease (CAD) patients undergoing coronary intervention, however non-P2Y12 mediated effects have also been observed. The thienopyridine-Clopidogrel, for example, forms S-nitrosothiols (RSNO) at low pH, in the presence of nitrite in-vitro but it is unclear whether this occurs substantially in-vivo. It is unknown whether the newer class of non-thienopyridine antiplatelets(ticagrelor) has similar properties. Dietary sources of inorganic nitrate (NO3-) are also known to provide alternative pathways for NO production. This thesis investigates the effect of dietary nitrate supplement with or without clopidogrel therapy on NO metabolites and platelet inhibition in CAD patients and explores the potential role of ticagrelor in RSNO biosynthesis. In vitro studies demonstrate dietary NO3- (in the form of SIS®-Go+ and Beet-It®) gets converted to nitrite via bacterial nitrate reductase and thereby readily formed S-nitrosothiols in the simulated acidic gastric medium with and without clopidogrel. In CAD patients, dietary NO3- (SIS® Go+) along with or without clopidogrel therapy results in a significant rise in plasma nitrate, nitrite and RSNO levels. NO3- + clopidogrel therapy caused significantly more inhibition of TRAP mediated platelet activation with patients receiving clopidogrel with little change in the ADP mediated platelet inhibition, suggesting a non-ADP mediated effect due to RSNO. Concomitant PPI therapy has no effect. Importantly, Ticagrelor has the ability to form RSNO in vitro and in-vivo. RSNO increased significantly in patients following a loading dose of Ticagrelor. However, elevated RSNO are not sustained in patients receiving a maintenance dose of Ticagrelor. In conclusion, dietary NO3- therapy significantly augments RSNO level with or without clopidogrel in CAD. Ticagrelor exhibits RSNO formation in-vitro and in CAD patients. Augmented RSNO may explain the P2Y12 independent effects seen with these agents and represents a novel therapeutic approach in future management of CAD.

Item Type: Thesis (MD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Date of First Compliant Deposit: 23 October 2019
Last Modified: 23 Oct 2019 16:18
URI: http://orca.cf.ac.uk/id/eprint/126166

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